Stress exposure during development is associated with mental illnesses that afflict veterans. Schizophrenia currently accounts for a staggering 19% of all veteran full disability cases, and depression and anxiety-related disorders such as post-traumatic stress disorder are common in veterans returning from service. Depressive disorders and schizophrenia have etiological links to both prenatal and adolescent periods of development. Importantly, adolescent brain development in humans extends into the early twenties (even 24 for some brain regions), which overlaps significantly with the time-frame for military service. Thus, increased scientific understanding of how stress during development impacts brain development and stress-related disorders is imperative to the health of our veterans. Despite recent clinical advances in identifying adolescents at high risk for psychosis, the ability of available models to accurately predict psychotic conversion is less than 30%, suggesting that unidentified factors are contributing significantly to an individual's risk for psychosis. One possible factor is the developmental stress history of an individual. While studies often account for adolescent stress exposure and/or cortisol levels when assigning a high risk designation, current models have not included stress experienced by individuals at earlier developmental time points. From the standpoint of sensitive periods of brain development, and individual's previous stressful experiences may alter the course of brain development in a manner that confers increased risk, or even resilience, to the impact of subsequent stressors. Despite the known relationships between stress exposure during prenatal and adolescent development and mental illness, whether prenatal stress exposure increases sensitivity to stress during adolescence is not known. Preclinical rodent models have enormous potential for elucidating the relationships between the timing of stress exposure across development and brain dysfunction. Therefore, Aim 1 will test the hypothesis that prenatal stress exposure programs the impact of adolescent stress on subsequent behavioral function in a sex-specific manner. This hypothesis predicts that (1) the combined effects of prenatal and adolescent stress on adult behavioral function will differ from the isolated effects of stress during either time period alone, (2) identical stressors experienced in adulthood will not result in the same magnitude of behavioral impairments (3) the behavioral effects of developmental stress will depend on the sex of the animals. Aim 2 will investigate the neural mechanisms by which developmental stress exposure impacts adult behavioral function. Hippocampal nicotinic receptor abnormalities are present in psychiatric illnesses such as depression and schizophrenia, and are important regulators of memory function and anxiety-related behaviors. Therefore, Aim 2 will test the hypothesis that stress-dependent behavioral changes are mediated by alterations in nicotinic receptor levels and/or function. This hypothesis predicts that levels and/or function of nicotinic receptors will vary as consequence of stress experienced prenatally or during adolescence. Ultimately, this work will advance our knowledge of the developmental and environmental factors contributing to individual differences in vulnerability to psychopathology, and allow for better targeting of the timeframe for prevention and intervention in our veterans. PUBLIC HEALTH RELEVANCE: Many psychiatric illnesses afflicting veterans are associated with stress exposure during early development and late adolescence. Indeed, disorders such as depression and schizophrenia typically develop during adolescence, which spans the ages most common for military service (17-24). Thus, understanding how stress exposure alters brain development and risk for mental disorders such as schizophrenia and depression is imperative to the health of veterans, especially during war time. The current studies investigate in a preclinical model the effects of stress during development on behavioral function, and whether stress-induced behavioral deficits are caused by changes in brain nicotinic receptors. The results of these studies are important for developing gender-specific interventions aimed at preventing and improving the debilitating symptoms of mental illnesses experienced by veterans.